CN1136855C - Cross-linked polymers for removing bile salts from patient - Google Patents

Cross-linked polymers for removing bile salts from patient Download PDF

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CN1136855C
CN1136855C CNB951935224A CN95193522A CN1136855C CN 1136855 C CN1136855 C CN 1136855C CN B951935224 A CNB951935224 A CN B951935224A CN 95193522 A CN95193522 A CN 95193522A CN 1136855 C CN1136855 C CN 1136855C
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CN1155287A (en
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W����������ά���
W·哈瑞·曼德维里·Ⅲ
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斯蒂芬·兰德尔·霍穆斯-法利
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Genzyme Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/795—Polymers containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/52—Amides or imides
    • C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F220/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S210/00—Liquid purification or separation
    • Y10S210/902—Materials removed
    • Y10S210/903—Nitrogenous

Abstract

A method for removing bile salts from a patient by ion exchange by administering to the patient a therapeutically effective amount of one or more highly crosslinked polymers characterized by a repeat unit having the formula or copolymer thereof, where n is an integer; R1 is H or a C1-C8 alkyl group; M is Z is O, NR3R, S, or (CH2)m; m=0-10; R3is H or a C1-C8 alkyl group; and R2 is where p=0-10, and each R4, R5, and R6, independently, is H, C1-C8 alkyl group, or an aryl group. The polymer is nontoxic and stable.

Description

Be used in patient's body, removing the cross linked polymer of bile salts
Background technology of the present invention
The present invention relates in patient's body, remove bile salts.
Chelating and remove bile salts (for example cholate, glycocholate, sweet Fel Anseris domestica hydrochlorate, middle sulphur cholate and dexycholate) and can reduce patient's cholesterol levels in patient's body.The ion exchange resin of removing bile salts after the process digestive system is taken is own through being used for this purpose.Remove bile salts and will cause producing in the body more bile salts.Because the bioprecursor of bile salts is a cholesterol, so cholesterol metabolism is the minimizing that bile salts is just followed the intravital cholesterol of ill people.
Technical scheme of the present invention
First aspect, the present invention is characterised in that the method for removing bile salts in patient's body by ion exchange, comprises one or more high cross linked polymers of taking nontoxic and stable treatment effective dose to the patient.Polymer is characterised in that to have the following formula repetitive Or its copolymer.
Wherein n is an integer; R 1Be H or C 1-C 8Alkyl (can be straight or branched, replacement or unsubstituted, methyl for example); M is
Figure C9519352200132
Or-Z-R 2Z is O, NR 3, S, or (CH 2) mM=0-10; R 3Be H or C 1-C 8Alkyl (can be straight or branched, replacement or unsubstituted, methyl for example); And R 2Be Or
Figure C9519352200142
Wherein P=0-10, and each R 4, R 5And R 6Each is H naturally, C 1-C 8Alkyl (can be straight or branched, replacement or unsubstituted, methyl for example), or aryl (for example have one or more rings and can be substituted or not be substituted, phenyl for example, naphthyl, imidazole radicals, or pyridine radicals).
" nontoxic " means when treatment effective dose when being digested, polymer or any to be discharged into intravital ion all be harmless.It is preferably, in fact this that to be discharged into intravital ion pair patient be favourable.For example, tradable ion is natural nutrition thing such as aminoacid.
" stablize " that mean can be not dissolved when being absorbed with the treatment effective dose when polymer, also do not decompose to be formed with harmful by-product, and be kept perfectly basically and excrete so that will finish the ion of ion exchange.
In preferred embodiment, polymer is finished by multi-functional cross-linking comonomer is crosslinked, and wherein the amount of comonomer is about the 1-25% (more preferably 2.5-20%) of per total wt.
Polymer also preferably includes one or more hydrophobic comonomers, styrene for example, vinyl naphthalene, vinyl xylene, ethyl vinyl benzene, the N-alkyl of acrylamide and Methacrylamide and N-aryl derivatives, alkyl acrylate and aryl ester, alkyl methacrylate and aryl ester, 4-vinyl xenyl, 4-vinyl methoxybenzene, 4-aminobenzene ethylene, with the fluorinated derivatives of any of these comonomer (for example to phenyl-monofluoride ethylene, perfluoro styrene, hexafluoro isopropylacrylic acid ester, hexafluoro butyl methyl acrylate, or 17 fluorine decyl methacrylates).Alkyl is preferably C 1-C 15Alkyl can be a straight chain, side chain or cyclic (for example cyclohexyl), and can further be substituted or not replacement.Aryl preferably has outer or a plurality of rings and can be substituted or do not replace, phenyl for example, naphthyl, imidazole radicals, or pyridine radicals.Polymer can also comprise the comonomer that one or more are positively charged, vinylpyridine for example, dimethylamino methyl styrene, or vinyl imidazole.
First preferred examples of polymer is characterised in that to have following formula repetitive or its copolymer
This polymer can also comprise that following one or more following compositions are as comonomer: n-butyl methyl acrylamide, hexafluoro butyl methyl acrylate, 17 fluorine decyl methacrylates, styrene or its fluorinated derivatives, the 2-vinyl naphthalene, the 4-vinyl imidazole, vinylpyridine, ethyl-methyl acrylate trimethylammonium, ethyl propylene acid esters trimethylammonium, 4-vinyl xenyl, 4-vinyl methoxybenzene, or 4-aminobenzene ethylene.
The example of second preferred polymers is characterised in that to have following formula repetitive or its copolymer
Figure C9519352200152
This polymer can comprise that following one or more following compositions are as comonomer: N-isopropylacrylamide, styrene or its fluoride, hexafluoro isopropylacrylic acid ester and ethyl-methyl acrylate trimethylammonium.
The example of the 3rd preferred polymers is characterised in that to have following formula repetitive or its copolymer
Figure C9519352200153
This polymer can also comprise that styrene or its fluorinated derivatives are as comonomer.
The example of the 4th preferred polymers is characterised in that to have following formula repetitive or its copolymer.
The example of the 5th preferred polymers is characterised in that to have following formula repetitive or its copolymer.
Figure C9519352200162
The example of the 6th preferred polymers is characterised in that to have following formula repetitive or its copolymer
Figure C9519352200163
This polymer can also comprise that ethyl vinyl styrene is as comonomer.
The 7th preferred polymers example is characterised in that to have following formula repetitive or its copolymer.
Figure C9519352200164
The 8th preferred polymers example is characterised in that to have following formula repetitive or its copolymer
This polymer can also comprise that styrene or its fluorinated derivatives are as comonomer.
Second aspect, the present invention is characterised in that the method for removing bile salts in patient's body by ion exchange, comprises one or more high cross linked polymers of the treatment effective dose of taking to the patient, this polymer has following formula repetitive or its copolymer,
Figure C9519352200171
Wherein n is an integer; R 1Be H or C 1-C 8Alkyl; L is-NH-or G is Or
Figure C9519352200174
And, each R 2, R 3And R 4The H that respectively does for oneself, C 1-C 8It is nontoxic and stable that alkyl, or aryl, this polymer are taken the back.
In preferred embodiment, polymer is crosslinked by multi-functional cross-linking comonomer, and wherein the amount of comonomer is about the 1-25% (more preferably 2.5-20%) of total monomer weight.This polymer also preferably includes one or more above-mentioned hydrophobic comonomers.
The example of first kind of preferred polymers is characterised in that to have following formula repetitive or its copolymer This polymer can also comprise that styrene or its fluorinated derivatives are as comonomer.
The example of second kind of preferred polymers is characterised in that to have following formula repetitive or its copolymer.
Figure C9519352200181
First and second aspects according to the present invention, polymer can have positive charge, perhaps can become electrically charged under the physiological pH after taking.For the latter, charged ion is at the electronegative equilibrium ion of taking the exchange of back binding energy and bile salts.If polymer has positive charge, then this polymer can be provided one or more tradable equilibrium ions.The example of suitable equilibrium ion comprises Cl -, Br -, CH 3OSO 3 -, HSO 4 -, HO 4 2-, HCO 3 -, CO 3 2-, acetate, lactate, succinate, propionate, butyrate, Ascorbate, citrate, maleate, folate, amino acid derivativges, nucleotide, lipoid, or phospholipid.Can be identical or different between the equilibrium ion.For example, polymer can contain two kinds of dissimilar equilibrium ions, and these two kinds of ions are used to remove bile salts by exchange.Also can take more than one polymer, these polymer have separately in conjunction with its different intrinsic charge equilibrium ions.
The present invention also comprises the therapeutic combination that is used to remove bile salts, and said composition comprises one or more above-mentioned polymer for the treatment of effective dose.
On the other hand, the present invention relates to high crosslinking polymer composition, said composition comprises the polymer with following repetitive
Figure C9519352200182
R wherein 1Be H or methyl, Q is-NH-(CH 2) 3-or-O-(CH 2) 2, n is an integer, and at least a vinyl naphthalene that is selected from, vinyl imidazole, styrene fluorinated derivatives, the additional comonomers of fluorinated alkyl methacrylate.
In some preferred embodiments in this respect, R 1Be methyl, Q is-NH-(CH 2) 3-.This polymer can also comprise as the ethyl propylene acid esters trimethylammonium of comonomer or ethyl-methyl acrylate trimethylammonium.In another preferred embodiment, Q is-O-(CH 2) 2
The example of suitable fluorinated styrenes derivant comprises right-fluorobenzene ethylene and phenyl-pentafluoride ethylene.The example of suitable fluorinated alkyl methacrylate comprises hexafluoro butyl methyl acrylate and 17 fluorine decyl methacrylates.
In another aspect of this invention, also relate to high crosslinking polymer composition, said composition comprises and is characterized as the polymer with following repetitive,
R wherein 1Be H or methyl, Q is-NH-(CH 2) 3-or-O-(CH 2) 2, n is an integer, and as (a) styrene (b) ethyl propylene acid esters trimethylammonium or ethyl-methyl acrylate trimethylammonium, the wherein R of additional comonomers 1Be methyl, Q is-NH-(CH 2) 3-.
Again on the one hand, the present invention relates to syntheticly have hydrophobic and the method high cross linked polymer of hydrophilic unit, this method is included in alcoholic solvent and exists down and react with hydrophilic monomer or hydrophobic monomer.
Another again aspect the present invention relates to the method for removing bile salts in patient's body, and this method comprises the product of taking the following material of treatment effective dose to the patient:
(a) have one or more high cross linked polymers of following formula repetitive:
Figure C9519352200192
And salt and copolymer, wherein n and m are integers, each R 1, R 2And R 3Each is H naturally, or C 1-C 8Alkyl; And
(b) at least a alkylating reagent.It is nontoxic and stable that this product is taken the back.
" salt " means the positively charged nitrogen-atoms that amine nitrogen is obtained after protonated in repetitive and combines with its electronegative equilibrium ion.
When " alkylating reagent " means and react with cross linked polymer, on one or more polymer nitrogen-atoms, be connected with alkyl or derivatives thereof (for example aralkyl, hydroxy alkyl, alkylammonium salt, alkylamide, or their conjugate) with covalent bond.
In preferred embodiment, this product is crosslinked by multi-functional cross-linking comonomer, and wherein comonomer is about the 1-25% (more preferably 2.5-20%) of total monomer weight.
First preferred polymers is characterised in that to have the following formula repetitive:
Figure C9519352200201
Or its salt or its copolymer.
Second preferred polymers is characterised in that to have the following formula repetitive: Or its salt or its copolymer.
Preferred alkyl reagent has formula RX, and wherein R is C 1-C 20Alkyl, C 1-C 20Hydroxy alkyl, C 1-C 20Aralkyl, C 1-C 20Alkylammonium, or C 1-C 20Alkyl amido, X comprise one or more electrophilic leaving groups." electrophilic leaving group " means during alkylation, can be crosslinked the metathetical group of nitrogen-atoms in the polymer.The example of preferred leaving group comprises halogenide, epoxide, toluene fulfonate, mesylate group.For example, for epoxide group, alkylated reaction will cause the open loop of three-membered ring's oxygen ring.
The example of preferred alkyl reagent comprises C 1-C 20Alkyl halide (normal-butyl halogen for example, just-hexyl halogen, just-octyl group halogen, just-decyl halogen, just-dodecyl halogen, just-myristyl halogen, just-octadecyl halogen, and conjugate); C 1-C 20Alkyl halide (for example 1,10-dihalo decane; C 1-C 20Hydroxy alkyl halogen (for example 11-halo-1-tip-nip); C 1-C 20Aralkyl halogen (for example benzyl halide); C 1-C 20Alkyl halide ammonium salt (for example (4-halogenated butyl) front three ammonium salt, (6-halo hexyl) front three ammonium salt, (8-halo octyl group) front three ammonium salt, (10-halo decyl) front three ammonium salt, (12-halo-dodecyl) front three ammonium salt and their conjugate); C 1-C 20Alkyl epoxy ammonium salt (for example (glycidyl propyl group) front three ammonium salt); And C 1-C 20Epoxy alkyl amide (for example N-(2, the 3-expoxy propane) butyramide, N-(2, the 3-expoxy propane) caproamide, and conjugate).
Polymer is particularly preferred with at least two kinds of alkylating reagent reactions.In a preferred embodiment, one of alkylating reagent is formula RX, and wherein R is C 1-C 20Alkyl, X comprise one or more hydrophilic leaving groups (for example alkyl halide), and another alkylating reagent is formula R ' X, and wherein R ' is C 1-C 20Alkyl ammonium group, X comprises one or more hydrophilic leaving groups (for example alkyl halide ammonium salt).
In another preferred embodiment, one of alkylating reagent is RX, and wherein R is C 1-C 20Alkyl, X comprise one or more hydrophilic leaving groups (for example alkyl halide), and another alkylating reagent is R ' X, and wherein R ' is C 1-C 20Hydroxy alkyl, X comprise one or more hydrophilic leaving groups (for example hydroxy alkyl halogen).
In another preferred embodiment, one of alkylating reagent is C 1-C 20Saturated dihalide, another alkylating reagent is C 1-C 20Alkylammonium salt.
The invention provides a kind of effective Therapeutic Method (thereby reducing patient's cholesterol level) of removing bile salts in patient's body.It is nontoxic also with stable taking this compositions with the treatment effective dose.
The present invention also provides the polymer of possess hydrophilic property and hydrophobic unit effectively synthetic, and promptly this is reflected under the alcoholic solvent existence and carries out, and this alcoholic solvent it has been generally acknowledged that the polymer solvent that is not good because its chain shifts character.
Further feature and advantage will be seen clearly from following preferred embodiment and claim.
Most preferred embodiment of the present invention Compositions
Preferred polymers has the structural formula that provides at the foregoing invention overview section.This polymer is high crosslinked.High crosslinked level makes the insoluble fully and restriction alkylation reaction product of polymer only at gastrointestinal tract activity be arranged.Therefore, said composition is non-system activity, will reduce the side effect to the patient like this.
Polymer is preferably by carrying out crosslinked adding cross-linking comonomer between polymerization period in reactant mixture.The example of suitable cross-linking comonomer comprises diacrylate and dimethylacrylate (ethylene glycol diacrylate for example, diacrylate propylene glycol ester, diacrylate butanediol ester, Ethylene glycol dimethacrylate, the dimethyl allene acid propylene glycol ester, tetramethylene dimethacrylate, dimethacrylate macrogol ester, the diacrylate macrogol ester), methylene bisacrylamide, the two Methacrylamides of methylene, inferior second bisacrylamide, the two Methacrylamides of inferior second, inferior second (H 3CH 2) two Methacrylamides, ethylenebis acrylamide, divinylbenzene, bisphenol a dimethacrylate, and bisphenol a diacrylate.These cross-linking comonomers promptly can be commodity also people such as available Mandeville " Process for Adjusting Ion Concentration in a Patient andCompositions Therefor; " U.S.S.N.08/065,113, described method preparation in May 20 1993 applying date (transferring the present patent application common assignee, incorporated by reference here).Typically, the amount of cross-linking agent is the 1.0-25% of cross-linking agent and total monomer weight, is preferably 2.5-20%.
Preferably, polymer comprises that one or more increase the total hydrophobic comonomer of polymer.Because bile salts is hydrophobic, hydrophobic monomer can make that interactional selectivity reaches maximum between polymer and the bile salts.
The example of suitable hydrophobic comonomer comprises, acrylamide for example, Methacrylamide, and N-alkyl (for example methyl, ethyl, isopropyl, butyl, hexyl, dodecyl, cyclohexyl, dicyclohexyl) and N-aryl (for example phenyl, diphenyl) derivant; Alkyl and aryl-acrylic acid esters and methacrylate (for example ethyl, propyl group, butyl, dodecyl), and fluorinated derivatives (for example hexafluoro isopropylacrylic acid ester, hexafluoro butyl methyl acrylate, 17 fluorine decyl acrylate); Styrene and derivant thereof (dimethylamino methyl styrene for example, 4 aminobenzene ethylene, and fluorinated derivatives, for example right-fluorobenzene ethylene, phenyl-pentafluoride ethylene); Vinyl xylene, ethyl vinyl benzene; Vinyl naphthalene; Vinylpyridine; Vinyl imidazole; 4-vinyl biphenyl, 4,4-vinyl methoxybenzene; And conjugate.The amount of used hydrophobic comonomer is a 1-75% weight in these polymer of preparation, preferred 3-65%.
Required hydrophobic level also can obtain easily by suitably selecting cross-linking comonomer.For example divinylbenzene is the cross-linking comonomer that suits and also is hydrophobic.In addition, main " impurity " in divinylbenzene is vinyl xylene, ethyl vinyl benzene, and this hydrophobic polymerisable comonomer is also made contributions to the total hydrophobicity of polymer.Other hydrophobicity cross-linking comonomer comprises bisphenol a diacrylate and bisphenol a dimethacrylate.
Cross linked polymer can react with one or more alkylating reagents.Oneself provides the example of preferred alkylating reagent in summary of the invention. A. the preparation of polymerThe preparation of embodiment 1. poly-(methacrylamido propyl group front three ammonium chloride) (poly-MAPTAC)
In flask at the bottom of the 3 neck gardens of 1000mL, add following material: methacrylamidopropyltrimethyl trimethyl ammonium chloride (MAPTAC) (40mL, 50% aqueous solution, 21g), Ethylene glycol dimethacrylate cross-linking comonomer (5.00g, 4.76mL), ethyl acetate (200mL), 2-propanol (200mL).Gained solution is clarifying.Then add polymerization initiator AIBN (0.1g) and reactant mixture is heated to 65 ℃.When temperature reached 65 ℃, with the solution degassing 5 minutes, at this moment solution became and mixes erosion with nitrogen, illustrated that polymerization carries out.To be reflected at 65 ℃ and keep again 3 hours, be cooled to room temperature then.
With resulting polymers (hard and sticking) and 500mL hydration and so that softening polymer, then it is transferred in the blender and with 1500mL 2-propanol blend and centrifugal.The decantation mixture also is transferred in another mixer by 100mL water.Add the 800mL2-propanol and mixture oozed and close, sedimentation is decantation then.Mixture and 1000mL2-propanol are merged, and fusion is filtered and vacuum drying, obtains the 12.6g polymer.
With the two crosslinked poly-MAPTAC of Methacrylamide cross-linking comonomer of similar approach preparation and 0.5% methylene, with the two crosslinked poly-MAPTAC of Methacrylamide cross-linking comonomer of 10% methylene; With with the crosslinked poly-MAPTAC of 10% divinyl benzene crosslinked comonomer.The preparation of embodiment 2. poly-(vinylamines)
The first step is the preparation of ethylenebis acetamide.With acetamide (118g), acetaldehyde (44.06g), copper acetate (0.2g), and water (300mL) is contained in 1L and has in condenser, thermometer and the churned mechanically three-neck flask.Add dense HCl (34mL) and mixture heated was stirred 24 hours to 45-50 ℃.Vacuum is removed to anhydrate and is obtained thick sludge, crystallization when it is cooled to 5 ℃.Add acetone (200mL) and also stir a few minutes, leach solid and discard.Propanol is cooled to 0 ℃ and leach solid.This solid with 500mL acetone rinsing and air drying 18 hours, is obtained 31.5g ethylenebis acetamide.
Second step is for to prepare vinyl acetamide from the ethylenebis acetamide, with ethylenebis acetamide (31.05g), phosphinylidyne calcium (2g) and kieselguhr 541 (2g) are packed in the 500mL three-neck flask of the still head that has thermometer, mechanical agitation and top Vigreux post.By the heating flask to 180-225 ℃ at 35mmHg vacuum distilling mixture.Collection also contains the one-component (10.8g) of most of acetamide (being measured by NMR) except product.This solid product is dissolved in isopropyl alcohol (30mL) to form polymerization crude ethylene yl acetamide solution.
With crude ethylene yl acetamide solution (15mL), divinylbenzene (1g, technical grade, purity 55%, mixed isomers), and mixed being incorporated in of AIBN (0.3g) is heated to backflow 90 minutes, the formation solid precipitation under the blanket of nitrogen.Cooling solution adds isopropyl alcohol (50mL), and with centrifugal collection solid.Wash this solid twice with isopropyl alcohol, water washes once, and drying obtains 0.8g poly-(vinyl acetamide) in vacuum tank, and this material is used to prepare following poly-(vinylamine).
To gather (vinyl acetamide) (0.79g) packs in the single neck flask of 100mL that contains water (25mL) and dense HCl (25mL).Mixture was refluxed 5 days, and leach solid, water washes once, and with isopropyl alcohol flushing twice, drying obtains the 0.77g product in vacuum tank.Infrared spectrum analysis shows to also have a large amount of amide (1656cm -1) exist, do not form a lot of amine (1606cm -1).Be suspended in reactant (about 0.84g) in NaOH (46g) and the water (46g) and be heated to boiling point (about 140 ℃).Because blowing temperature is lowered, be maintained at about 100 ℃ 2 hours.Add water (100mL) and solid collected by filtration.Water flushing solid is suspended in it in water (500mL) and with acetic acid after once and regulates pH to 5.Leach solid again, water, isopropyl alcohol flushing, and drying obtains the 0.51g product in vacuum tank.Infrared spectrum analysis shows and is split into a large amount of amine.Embodiment 3. poly-(3-dimethylamino propyl acrylamide) preparations (DMAPA)
In the 100mL three-neck flask, dimethylamino propyl acrylamide (10g) and methylene bisacrylamide cross-linking comonomer (1.1g) are dissolved in the 50mL water.This solution was stirred 10 minutes under nitrogen.Potassium peroxydisulfate (0.3g) and sodium metabisulfite (0.3g) are dissolved in mixing then in the 2-3mL water respectively.Still under nitrogen, above-mentioned solution is added in the monomer solution after several seconds.At this moment form jelly immediately and spent the night by being put.Remove jelly and mix with the 500mL isopropyl alcohol.Leach solid and use acetone rinsing three times.Leach the white solid powder and in vacuum tank drying obtain 6.1g.Embodiment 4. poly-(dimethylamino propyl acrylamide hydrochloride) preparations (DMAPAHCl)
Dimethylamino propyl acrylamide (20.10g) is dissolved in the water (100mL) and is neutralized to pH6.95 with dense HCl.Add methylene bisacrylamide cross-linking comonomer (2.2g) and water (100mL) and warm (34 °) so that dissolving.Under agitation add potassium peroxydisulfate (0.2g) and inclined to one side Potassium acid sulfite (0.2g).After the gelation, solution was placed 6 hours, and mixed 3 times with isopropyl alcohol (600mL), drying obtains the 14.47g title polymer in the vacuum tank.
With the two crosslinked poly-DMAPAHCl of Methacrylamide cross-linking comonomer of similar approach preparation and 10% methylene.Embodiment 5. poly-(dimethylamino-propyl Methacrylamide hydrochloride) (DMAPMA.HCl)
Preparation
Dimethylamino-propyl methacrylic acid amino (20.0g) is dissolved in the water (100mL) and is neutralized to pH6.94 with dense HCl.Add methylene bisacrylamide cross-linking comonomer (2.2g) and with this solution warm (39 ℃) so that dissolving.Under stirring and blanket of nitrogen, add potassium peroxydisulfate (0.3g) and inclined to one side thionyl hydrogen potassium (0.3g).After the gelation, the solution placement is spent the night, and mix twice with isopropyl alcohol (500mL), drying obtains the 27.65g product in the vacuum tank.With some solid (3.2g; Sieve with-80/+200 mesh sieve) in water (100mL), stirred 50 minutes.Add water (100mL) again and with solution stirring 36 minutes.Centrifugal collection solid is resuspended in the water (400mL), stirs centrifugal again collection solid 15 minutes.At last with solid suspension in water (500mL), stirred 90 minutes, filter to collect.Solid drying in vacuum tank is drawn the 0.28g title polymer.Embodiment 6. poly-(methacrylamidopropyltrimethyl trimethyl ammonium chloride) copolymerization (just-butyl methyl third
The alkene amide) (the preparation of MAPTAC copolymerization-BuMA)
Comonomer just-butyl methyl acrylamide (BuMA) is prepared as follows:
In the 1L flask, (48.4mL, 52.3g 0.500mol) are dissolved in the oxolane (300mL) and place it in the ice bath with methacrylic chloride.When keeping 5-15 ℃ of temperature, drip the solution that contains butylamine (36.6g) and triethylamine (55.6g).With solution stirring after 5 minutes, leach solid triethylamine salt acidulants and discard.Solvent removed in vacuo and the gained yellow oil is used for down step preparation from mother solution need not to be further purified.Produce 71.58g BuMA comonomer.
In flask at the bottom of the 1000mL three neck gardens, add following material: methacrylamidopropyltrimethyl trimethyl ammonium chloride (MAPTAC) (108mL, 50% aqueous solution, 56.8g), Ethylene glycol dimethacrylate cross-linking comonomer (19.62g), BuMA comonomer (12.12g) and 2-propanol (850mL).Gained solution is clarifying.Then reactant mixture is heated to 40 ℃, outgases with nitrogen simultaneously.When solution reaches 40 ℃, add catalyst, i.e. the potassium peroxydisulfate (0.75g) and the 25mL aqueous solution of potassium acid sulfate (0.75g) partially.At this moment solution begins to become muddy immediately, shows that polymerization carries out.To be reflected at 40 ℃ and keep 24 hours, be cooled to room temperature then.
Filter resulting polymers and use washed with isopropyl alcohol on funnel, vacuum drying obtains the 64.54g title polymer.
The polymer that will be used to test is used 800mL water washing totally twice at every turn, uses 500mL methanol wash twice subsequently at every turn, obtains the polymer that the 34.5g purification is crossed.
Crosslinked MAPTAC copolymerization-BuMA copolymer also is used as the dimethyl allene acid propylene glycol ester preparation of cross-linking comonomer, rather than prepares with Ethylene glycol dimethacrylate, is prepared as follows:
In flask at the bottom of the 1000mL three neck gardens, add following material: methacrylamidopropyltrimethyl trimethyl ammonium chloride (MAPTAC) (60mL, 50% aqueous solution, 31.5g), dimethyl allene acid propylene glycol ester cross-linking comonomer (9.81g), BuMA comonomer (6.06g) and 2-propanol (300mL).Gained solution is clarifying.Then reactant mixture is heated to 70 ℃, outgases with nitrogen simultaneously.When solution is heated to 70 ℃, add catalyst A IBN (0.50g).At this moment solution begins to become muddy immediately, illustrates that polymerization carries out.To be reflected at 70 ℃ and keep being cooled to then in 6 hours room temperature.
Filter resulting polymers and use washed with isopropyl alcohol on funnel, vacuum drying obtains the 23.3g polymer.
With similar approach and by adjusting the ratio preparation and the crosslinked MAPTAC copolymerization BuMA (5%) of 24% Ethylene glycol dimethacrylate cross-linking comonomer of initial monomers, with the crosslinked MAPTAC copolymerization BuMA (2%) of the two Methacrylamide cross-linking comonomers of 0.5% methylene and with the crosslinked MAPTAC copolymerization BuMA (14%) of 22% dimethyl allene acid propylene glycol ester cross-linking comonomer.Embodiment 7. poly-(methacrylamidopropyltrimethyl trimethyl ammonium chloride) copolymerization (styrene)
The preparation of (MAPTAC co polystyrene)
In flask at the bottom of the 1000mL three neck gardens, add following material, methacrylamidopropyltrimethyl trimethyl ammonium chloride (MAPTAC) (60mL, 50% aqueous solution, 31.5g), divinyl benzene crosslinked comonomer (2.00g), styrene copolymerized monomer (1.75g) and 2-propanol (300mL).Gained solution is clarifying.Then reactant mixture is heated to 60 ℃, and outgas with nitrogen.When solution temperature reaches 60 ℃, add catalyst A IBN (0.50g).At this moment this solution begins to become muddy immediately, illustrates that polymerization carries out.To be reflected at 60 ℃ and keep 24 hours, be cooled to room temperature then.After 7 hours, this mixture very thickness that becomes is for better the stirring adds the 100mL isopropyl alcohol.
Filter resulting polymers and use washed with isopropyl alcohol on funnel, vacuum drying obtains the 30.9g title polymer.
The polymer that will be used to test is used 1000mL water washing twice at every turn, then obtains the 28.0g polymer that purification is crossed for twice with the 800mL methanol wash at every turn.
With similar approach and by changing the ratio preparation and the crosslinked MAPTAC copolymerization-styrene (19%) of 7.5% tetramethylene dimethacrylate cross-linking comonomer of initial monomers, with the crosslinked MAPTAC copolymerization-styrene (23%) of 7% divinylbenzene comonomer, with the crosslinked MAPTAC copolymerization-styrene (30%) of 6% divinylbenzene comonomer and with the crosslinked MAPTAC copolymerization-styrene (38%) of 6% divinylbenzene comonomer.Embodiment 8. poly-(methacrylamidopropyltrimethyl trimethyl ammonium chloride) copolymerization (vinyl naphthalene)
(the preparation of MAPTAC copolymerization-VN)
In flask at the bottom of the 1000mL three neck gardens, add following material: methacrylamidopropyltrimethyl trimethyl ammonium chloride (MAPTAC) (50% aqueous solution of 40mL, 21.0g), divinyl benzene crosslinked comonomer (2.25g), 2-vinyl naphthalene comonomer (10.5g) and 2-propanol (320mL).Gained solution is clarifying.Then reactant mixture is heated to 65 ℃, outgases with nitrogen simultaneously.When solution reaches 65 ℃, add catalyst A IBN (0.50g).At this moment solution begins to become muddy immediately, illustrates that polymerization carries out.To be reflected at 65 ℃ and keep 20 hours, be cooled to room temperature then.
Filter resulting polymers and on funnel, wash pulp in the 400mL distilled water immediately then with isopropyl alcohol.Mixture is stirred filtration then in 0.5 hour.Repeat water washing once.With filter cake pulp and stirring 0.5 hour in 400mL methanol.Filtering mixt also repeats the methanol pulp once.Vacuum drying obtains 22.11g, 65.5% title polymer.
Prepare and the crosslinked MAPTAC copolymerization-VN (39%) of 5% divinyl benzene crosslinked comonomer by the ratio that changes initial monomers with similar approach.Embodiment 9. poly-(methacrylamidopropyltrimethyl trimethyl ammonium chloride) copolymerization (1-vinyl imidazole)
(the preparation of MAPTAC copolymerization-VI)
In flask at the bottom of the 1000mL three neck gardens, add following material: methacrylamidopropyltrimethyl trimethyl ammonium chloride (MAPTAC) (50% aqueous solution of 40mL, 21.0g), divinyl benzene crosslinked comonomer (2.25g), 1-vinyl imidazole comonomer (12.54g) and 2-propanol (300mL).Gained solution is clarifying.Then reactant mixture is heated to 65 ℃, outgases with nitrogen simultaneously.When solution reaches 65 ℃, add catalyst A IBN (0.50g).At this moment solution begins to become muddy immediately, illustrates that polymerization carries out.To be reflected at 65 ℃ and keep 20 hours, be cooled to room temperature then.
Filter resulting polymers and on funnel, wash pulp in the 400mL distilled water immediately then with isopropyl alcohol.Mixture is stirred filtration then in 0.5 hour.Repeat water washing once.With filter cake pulp and stirring 0.5 hour in 400mL methanol.Filtering mixt also repeats the methanol pulp once.Vacuum drying obtains 7.34g, 20.5% title polymer.Embodiment 10. poly-(trimethyl ammonium chloride ethyl acrylate) copolymerization (styrene) (the TMAEAC copolymerization-
Sty) preparation
In flask at the bottom of the 1000mL three neck gardens, add following material: trimethyl ammonium chloride ethyl acrylate (TMAEAC) (50% aqueous solution of 99.4mL, 53.0g), divinyl benzene crosslinked comonomer (7.00g), styrene copolymerized monomer (40.0g) and 2-propanol (800mL).Gained solution is clarifying.Then reactant mixture is heated to 65 ℃, outgases with nitrogen simultaneously.When solution reaches 65 ℃, add catalyst A IBN (1.50g).At this moment solution begins to become muddy immediately, illustrates that polymerization carries out.To be reflected at 65 ℃ and keep 6 hours, be cooled to 60 ℃ and restir 18 hours, be cooled to room temperature then.
Filter resulting polymers and on funnel, wash pulp in the 1000mL distilled water immediately then with isopropyl alcohol.Mixture stirred added 800mL methanol and restir in 0.5 hour then 0.5 hour.With mixture sedimentation and decantation supernatant, obtain the 750mL residue.With residue reuse 750mL methanol pulp and stirred 0.5 hour.The each 800mL of using methanol repeats methanol pulp and decantation twice.Add the 800mL isopropyl alcohol subsequently, mixture was stirred 0.5 hour and filtered.Add the 600mL isopropyl alcohol at last and stirred 0.5 hour.Vacuum drying filtrate obtains 49.2g, 49.2% title polymer.
With the crosslinked TMAEAC copolymerization-styrene (31%) of the ratio preparation of similar approach by changing initial monomers and 8% divinyl benzene crosslinked comonomer and with the crosslinked TMAEAC copolymerization-styrene (46%) of 6% divinyl benzene crosslinked comonomer.Embodiment 11. poly-(trimethyl ammonium chloride ethyl methacrylate) copolymerization (styrene) (TMAEMC
Copolymerization-styrene) preparation
In flask at the bottom of the 1000mL three neck gardens, add following material: trimethyl ammonium chloride ethyl methacrylate (TMAEMAC) (50% aqueous solution of 38.8mL, 21.7g), divinyl benzene crosslinked comonomer (3.72g), styrene copolymerized monomer (15.66g) and 2-propanol (2500mL).Gained solution is clarifying.Then reactant mixture is heated to 65 ℃, outgases with nitrogen simultaneously.When solution reaches 65 ℃, add catalyst A IBN (0.50g).At this moment solution begins to become muddy immediately, illustrates that polymerization carries out.The mixture very thickness that becomes adds the 100mL isopropyl alcohol again after 2 hours.After 5 hours, the mixture very thickness that becomes once more is so add the 100mL isopropyl alcohol again.To be reflected at 65 ℃ and keep 6 hours, be cooled to room temperature then.
Filter resulting polymers and on funnel, wash pulp in the 1000mL distilled water immediately then with isopropyl alcohol.Mixture stirred be transferred in the blender then in 0.5 hour and mixed 5 minutes.Filter polymer pulpous state thing and add the 1000mL distilled water and also again mixture was stirred 0.5 hour.Filtering mixt is used twice of 500mL methanol pulp filter cake at every turn.Vacuum drying filtrate obtains 30.2g, 75.9% title polymer.
With similar approach by changing the ratio preparation and the crosslinked TMAEMC copolymerization-styrene (58%) of 4% divinyl benzene crosslinked comonomer of initial monomers, with the crosslinked TMAEMC copolymerization-styrene (33%) of 4% divinyl benzene crosslinked comonomer and with the crosslinked TMAEMC copolymerization-styrene (24%) of 4% divinyl benzene crosslinked comonomer.Embodiment 12. poly-(methacrylamido propyl group-3-(trimethyl ammonium chloride)), and copolymerization (2,3,4,5,6-
Five fluoride-based styrene) (MAPTAC copolymerization-StyF 5) preparation
Add following material in flask at the bottom of the 1000mL three neck gardens: methacrylamido propyl group-3-(trimethyl ammonium chloride) is (50% aqueous solution of 24.5mL (MAPTAC), 13.00g), divinyl benzene crosslinked comonomer (1.00g), phenyl-pentafluoride ethylene comonomer (6.00g) and 2-propanol (150mL) and AIBN (0.50g).Gained solution is clarifying.Then reactant mixture is heated to 65 ℃, outgases with nitrogen simultaneously.Solution begins to become muddy after very short a period of time, illustrates that polymerization carries out.The mixture very thickness that becomes after 5 hours is so add the 100mL isopropyl alcohol again.To be reflected at 65 ℃ and keep 24 hours, be cooled to room temperature then.
Filter resulting polymers and on funnel, wash pulp in the 500mL distilled water immediately then with isopropyl alcohol.Mixture was stirred 0.5 hour, add the 500mL distilled water and mixture was stirred 0.5 hour.Filter polymer, and filter cake is used twice of 300mL methanol pulp at every turn.Vacuum drying filtrate obtains the 7.74g title polymer.
Prepare and the crosslinked MAPTAC copolymerization-StyF of 5% divinyl benzene crosslinked comonomer by the ratio that changes initial monomers with similar approach 5(20%), with the crosslinked MAPTAC copolymerization-StyF of 5% divinyl benzene crosslinked comonomer 5(40%) and with the crosslinked MAPTAC copolymerization-StyF of 5% divinyl benzene crosslinked comonomer 5(45%).Embodiment 13. poly-(methacrylamido propyl group-3-(trimethyl ammonium chloride)), copolymerization 2-(trimethyl
Ammonium chloride) ethyl methacrylate copolymerization-styrene (the MAPTAC copolymerization-
The preparation of TMAEMC copolymerization-Sty)
Add following material in flask at the bottom of the 1000mL three neck gardens: methacrylamido propyl group-3-(trimethyl ammonium chloride) is (50% aqueous solution of 10.40g (MAPTAC), 5.20g), 2-(trimethyl ammonium chloride) ethyl methacrylate (TMAEMC) (4.86g, 70% aqueous solution, 3.40g), divinyl benzene crosslinked comonomer (1.00g), styrene copolymerized monomer (10.40g), 2-propanol (150mL) and AIBN (0.50g).Gained solution is clarifying.Then reactant mixture is heated to 70 ℃, outgases with nitrogen simultaneously.Solution begins to become muddy after very short a period of time, illustrates that polymerization carries out.To be reflected at 70 ℃ and keep 24 hours, be cooled to room temperature then.
Filter resulting polymers and on funnel, wash pulp in 500mL methanol immediately then with isopropyl alcohol.Mixture was stirred 0.5 hour.Filter polymer pulpous state thing and add the 400mL distilled water and also again mixture was stirred 0.5 hour.The filtering mixt rehydration pulp of laying equal stress on.Filtering mixt is also used twice of 400mL methanol pulp with filter cake at every turn.Vacuum drying filtrate obtains the 5.39g title polymer.
Prepare and crosslinked MAPTAC copolymerization-TMAEMC (34%) copolymerization-Sty (36%) of 5% divinyl benzene crosslinked comonomer by the ratio that changes initial monomers with similar approach, with crosslinked MAPTAC copolymerization-TMAEMC (31%) copolymerization-Sty (41%) of 5% divinyl benzene crosslinked comonomer, with crosslinked MAPTAC copolymerization-TMAEMC (28%) copolymerization-Sty (46%) of 5% divinyl benzene crosslinked comonomer, with crosslinked MAPTAC copolymerization-TMAEMC (23%) copolymerization-Sty (48%) of 5% divinyl benzene crosslinked comonomer, with crosslinked MAPTAC copolymerization-TMAEMC (26%) copolymerization-Sty (52%) of 4% divinyl benzene crosslinked comonomer, with crosslinked MAPTAC copolymerization-TMAEMC (17%) copolymerization-Sty (53%) of 4% divinyl benzene crosslinked comonomer, with crosslinked MAPTAC copolymerization-TMAEMC (15%) copolymerization-Sty (55%) of 4% divinyl benzene crosslinked comonomer, with crosslinked MAPTAC copolymerization-TMAEMC (13%) copolymerization-Sty (61.5%) of 4% divinyl benzene crosslinked comonomer.Embodiment 14. poly-(trimethyl ammonium chloride ethyl methacrylate copolymerization-(N-isopropylacrylamide))
(the preparation of TMAEMAC copolymerization-IPA)
At first, being prepared as follows of comonomer N-isopropylacrylamide (IPA):
(63mL, 70.2g 0.775mol) are dissolved in oxolane (200mL) and place ice bath with acryloyl chloride in the 1L flask.Dropping contains 2-aminopropane., and (1.50mol) solution maintains the temperature at 5-15 ℃ for 127.7mL, 88.67g.With solution stirring after 10 minutes with the filtering of solid isopropyl amine salt acidulants.Solvent removed in vacuo from mother solution obtains almost colourless oil, through placing it is solidified, and need not to be further purified the preparation that promptly can be used for following title copolymer.
In flask at the bottom of the 1000mL three neck gardens, add following material: trimethyl ammonium chloride ethyl methacrylate (50% aqueous solution of 76.5mL, 41.18g, 0.213mol), methylene-bisacrylamide cross-linking comonomer (2.40g), IPA comonomer (4.52g, 0.070mol), and water (200mL).Gained solution is clarifying.Stirred reaction mixture outgases with nitrogen simultaneously.When outgasing, solution adds the catalyst that potassium peroxydisulfate (0.3g) and pyrophosphorous acid potassium (0.3g) are formed.Polyreaction began after 2 minutes, condensed into glue after 3 minutes.
In second day morning, forward to this glue in the mixer and add 1000mL water.Mix the whole water of a few post polymerization thing inspirations in second.Expansible polymer divides several to mix several times with its dehydration with isopropyl alcohol.Filter resulting polymers and also wash on funnel with isopropyl alcohol, vacuum drying filtrate obtains 36.8g title copolymer.Embodiment 15. poly-(methacrylamido propyl group-3-(trimethyl ammonium chloride)) copolymerization-(vinylpyridines)
(the preparation of MAPTAC copolymerization-VP)
Add following material in flask at the bottom of the 1000mL three neck gardens: methacrylamido propyl group-3-(trimethyl ammonium chloride) is (50% aqueous solution of 40mL (MAPTAC), 21.0g), divinyl benzene crosslinked comonomer (2.25g), vinylpyridine (14.0g, 0.133mol), concentrated hydrochloric acid (11mL, 0.133mol), 2-propanol (300mL), and AIBN (0.67g).Gained solution is clarifying.Then, reactant mixture is heated to 60 ℃, outgases with nitrogen simultaneously.This solution begins muddiness after short time, shows that polyreaction carries out.Reactant mixture was kept 20 hours at 60 ℃, be cooled to room temperature then.
Filter resulting polymers and on funnel, use washed with isopropyl alcohol, pulp in the 1000mL distilled water immediately then.Mixture was stirred 1 hour.Filter polymer slurries, on funnel, use methanol wash, pulp 1 hour in 600mL methanol then.Filter and air drying, obtain the 20.4g copolymer.Embodiment 16. poly-(trimethyl ammonium chloride ethyl methacrylate) copolymerization-(to the fluorobenzene ethylene)
(TMAEMC copolymerization-F 1Sty) preparation
In the 500mL flask, add following material: trimethyl ammonium chloride ethyl methacrylate (TMAEMC) (70% aqueous solution of 11.0g, 7.70g), divinyl benzene crosslinked comonomer (0.50g), to fluorobenzene ethylene comonomer (4.00g), 2-propanol (125mL) and AIBN (0.25g).Gained solution is clarifying.Then, reactant mixture is heated to 65 ℃, outgases with nitrogen simultaneously.The solution muddiness that will begin in a minute shows that polyreaction carries out.Be reflected at 65 ℃ and kept 6 hours, be cooled to room temperature then.
Except that desolvating, polymer is pulp in the 250mL distilled water immediately by decantation.Stirred this mixture 0.5 hour, then decantation.So the water pulp is 3 times.At last, with 400mL methanol pulp polymer.Filter and vacuum drying, obtain 5.42g, 44.4% title copolymer.
Prepare and the crosslinked TMAEMC copolymerization-F of 4% divinyl benzene crosslinked comonomer by the ratio that changes initial monomers with similar approach 1Sty (24%).Embodiment 17. poly-(methacrylamido propyl group-3-(trimethyl ammonium chloride)) copolymerization-(hexafluoro methyl-prop
The olefin(e) acid butyl ester) (MAPTAC copolymerization-F 6BMA) preparation
Add following material in flask at the bottom of the 1000mL three neck gardens: methacrylamido propyl group-3-(trimethyl ammonium chloride) is (50% aqueous solution of 28.5mL (MAPTAC), 15.0g), divinyl benzene crosslinked comonomer (1.00g), hexafluoro butyl methacrylate (4.00g), 2-propanol (150mL) and AIBN (0.50g).Gained solution is clarifying.Then, reactant mixture is heated to 60 ℃, outgases with nitrogen simultaneously.Solution begins muddiness after short time, shows that polyreaction carries out.Be reflected at 60 ℃ and kept 24 hours, be cooled to room temperature then.
Resulting polymers is filtered and on funnel, use washed with isopropyl alcohol, use the pulp of 500mL distilled water immediately.Mixture was stirred 1 hour.Filter polymer slurries, and the reuse water slurryization once.With polymer pulp 1 hour and filtration in 500mL methanol, and repeat once.At last the pulp in the 400mL isopropyl alcohol of this mixture is also stirred and spend the night.Filter and air drying, obtain 7.52g title copolymer.Embodiment 18. poly-(trimethyl ammonium chloride ethyl acrylate) copolymerization-(hexafluoropropene isopropyl propionates)
(TMAEAC copolymerization-F 6IA) preparation
In flask at the bottom of the 1000mL three neck gardens, add following material: the trimethyl ammonium chloride ethyl acrylate (50% aqueous solution of 30.0mL, 15.0g), divinyl benzene crosslinked comonomer (1.00g), F 6IPA (4.00g), AIBN (0.50g) and 2-propanol (150mL).Gained solution is clarifying.Reactant mixture is stirred,, and be heated to 60 ℃ simultaneously with the nitrogen degassing.The afterreaction mixture allowed to be cooled to room temperature in 18 hours, and decantation removes and desolvates.Remaining polymer pulp in 400mL water stirs 1 hour after-filtration.The reuse water slurryization is once used twice of methanol pulp then.At last, with polymer pulp in the 200mL isopropyl alcohol, stirred 2 hours and filtered.Air drying obtains the 5.59g title polymer.Embodiment 19. poly-(methacrylamido propyl group-3-(trimethyl ammonium chloride)) copolymerization-(17 methyl fluorides
Decyl acrylate) (MAPTAC copolymerization-F 17DecMA) preparation
Add following material in flask at the bottom of the 1000mL three neck gardens: methacrylamido propyl group-3-(trimethyl ammonium chloride) is (50% aqueous solution of 28.5mL (MAPTAC), 15.0g), divinyl benzene crosslinked comonomer (1.00g), 17 methyl fluoride decyl acrylates (4.00g), 2-propanol (1 50mL) and AIBN (0.40g).Gained solution is clarifying.Then, reactant mixture is heated to 65 ℃, outgases with nitrogen simultaneously.Solution begins muddiness after short time, shows that polyreaction carries out.The afterreaction mixture was very thick in 4 hours, added the 100mL isopropyl alcohol again, will be reflected at 65 ℃ and keep 18 hours, was cooled to room temperature then.
Filter resulting polymers, and on funnel, use washed with isopropyl alcohol, pulp in the 600mL distilled water immediately then.Mixture was stirred 1 hour.Filter polymer slurries, the reuse water slurryization once.Then with mixture pulp 1 hour and filtration in 500mL methanol.Air drying obtains the 17.73g title polymer.Embodiment 20. poly-(methacrylamido propyl group-3-(trimethyl ammonium chloride)) copolymerization-(2-(trimethyl chlorine
Change ammonium) ethyl acrylate), (MAPTAC copolymerization-TMAEAC is common for copolymerization-styrene
Poly--Sty) preparation
Add following material in flask at the bottom of the 1000mL three neck gardens: methacrylamido propyl group-3-(trimethyl ammonium chloride) is (50% aqueous solution of 10.00g (MAPTAC), 5.00g), 2-(trimethyl ammonium chloride) ethyl acrylate (TMAEAC) (50% aqueous solution of 6.00g, 3.00g), divinyl benzene crosslinked comonomer (1.00g), styrene (11.00g), 2-propanol (150mL) and AIBN (0.25g).Gained solution is clarifying.Then, reactant mixture is heated to 70 ℃, outgases with nitrogen simultaneously.Solution begins muddiness after short time, shows that polyreaction carries out.To be reflected at 70 ℃ and keep 24 hours, be cooled to room temperature then.
Filter resulting polymers, and on funnel, use washed with isopropyl alcohol, pulp in 500mL methanol immediately then.Mixture was stirred 0.5 hour.Sedimentation and decantation polymer slurries.Add the 200mL distilled water and mixture was stirred 0.5 hour.The decantation mixture, and then with the 400mL water slurryization.Decantation mixture, polymer are used twice of 200mL methanol pulp at every turn.Filter and air drying, obtain 2.76g title copolymer.
Prepare and crosslinked MAPTAC copolymerization-TMAEAC (10%) copolymerization-Sty (60%) of 5% divinyl benzene crosslinked comonomer by the ratio that changes initial monomers with similar approach.Embodiment 21. poly-(2-(trimethyl ammonium chloride) ethyl acrylate), copolymerization-(2,3,4,5,6-phenyl-pentafluoride ethylene)
(TMAEAC copolymerization-StyF 5) preparation
In flask at the bottom of the 1000mL three neck gardens, add following material: 2-(trimethyl ammonium chloride) ethyl acrylate (TMAEAC) (50% aqueous solution of 24.0mL, 13.00g), divinyl benzene crosslinked comonomer (1.00g), phenyl-pentafluoride ethylene (6.00g), 2-propanol (150mL) and AIBN (0.50g).Gained solution is clarifying.Then, reactant mixture is heated to 65 ℃, outgases with nitrogen simultaneously.Solution begins muddiness after short time, shows that polyreaction carries out.Mixture is very thick after 2 hours, therefore adds the 100mL isopropyl alcohol.To be reflected at 65 ℃ and keep 22 hours, be cooled to room temperature then.
Filter resulting polymers, and on funnel, use washed with isopropyl alcohol, pulp in the 400mL distilled water immediately then.Mixture was stirred 0.5 hour.Polymer slurries is filtered and adding 600mL distilled water, again mixture was stirred 0.5 hour.Filtering mixt, filter cake pulp in 400mL methanol.Filter and air drying, obtain 7.26g title copolymer.
Prepare and the crosslinked TMAEAC copolymerization-StyF of 5% divinyl benzene crosslinked comonomer by the ratio that changes initial monomers with similar approach 5(20%).Embodiment 22. poly-(2-(trimethyl ammonium chloride) ethyl methacrylate), copolymerization-(2,3,4,5, the 6-phenyl-pentafluoride
Ethylene) (TMAEMC copolymerization-StyF 5) preparation
In flask at the bottom of the 1000mL three neck gardens, add following material: 2-(trimethyl ammonium chloride) ethyl methacrylate (TMAEMC) (70% aqueous solution of 19.52mL, 13.66g), divinyl benzene crosslinked comonomer (1.00g), phenyl-pentafluoride ethylene (9.18g), 2-propanol (150mL) and AIBN (0.40g).Gained solution is clarifying.Then, reactant mixture is heated to 70 ℃, outgases with nitrogen simultaneously.Solution begins muddiness after short time, shows that polyreaction carries out.1.5 mixture is very thick after hour, therefore adds the 50mL isopropyl alcohol.To be reflected at 70 ℃ and keep 5 hours, be cooled to room temperature then.
Filter resulting polymers, and on funnel, use washed with isopropyl alcohol, pulp in the 500mL distilled water immediately then.Mixture was stirred 0.25 hour.Polymer slurries is filtered and adding 500mL distilled water, again mixture was stirred 0.25 hour.Polymer reuse water slurryization once.The pulp three times in the methanol of each 300mL of filtering mixt, filter cake.Filter and air drying, obtain 1.26g title copolymer.
Prepare and the crosslinked TMAEMC copolymerization-StyF of 4% divinyl benzene crosslinked comonomer by the ratio that changes initial monomers with similar approach 5(24%) and with the crosslinked TMAEMC copolymerization-StyF of 4% divinyl benzene crosslinked comonomer 5(39%).The preparation of embodiment 23. poly-(ethylene imines)
To gather ethylene imine (50% aqueous solution of 120g; Scientific Polymer Products) is dissolved in water (250mL).Drip chloropropylene oxide (22.1mL).With solution be heated to 60 ℃ 4 hours.Afterwards, form colloid.Shift out colloid, water (1.5L) blending, and leach solid, water (3L) rinsing three times and with twice of isopropyl alcohol (3L) rinsing.The gained colloid is dry in vacuum drying oven, obtains the 81.2g title polymer.Embodiment 24. poly-(methacrylamido propyl group-3-(trimethyl ammonium chloride)), copolymerization-(2-(trimethyl
Ammonium chloride) ethyl methacrylate), copolymerization-(2,3,4,5,6-phenyl-pentafluoride ethylene)
(MAPTAC copolymerization-TMAEMC copolymerization-StyF 5) preparation
Add following material in flask at the bottom of the 1000mL three neck gardens: methacrylamido propyl group-3-(trimethyl ammonium chloride) is (50% aqueous solution of 10.00g (MAPTAC), 5.00g), 2-(trimethyl ammonium chloride) ethyl methacrylate (TMAEMC) (70% aqueous solution of 5.71g, 4.00g), divinyl benzene crosslinked comonomer (1.00g), phenyl-pentafluoride ethylene (10.00g), 2-propanol (1 50mL) and AIBN (0.50g).Gained solution is clarifying.Then, reactant mixture is heated to 70 ℃, outgases with nitrogen simultaneously.Solution begins muddiness after short time, shows that polyreaction carries out.To be reflected at 70 ℃ and keep 24 hours, be cooled to room temperature then.
Filter resulting polymers, and on funnel, use washed with isopropyl alcohol, pulp in 500mL methanol immediately then.Mixture was stirred 0.25 hour.Filter polymer paste, use the 300mL water slurryization then, totally three times at every turn.Last polymer paste stirred close 5 minutes.Filtering mixt is used 300mL methanol pulp filter cake, twice totally then at every turn.Filter and vacuum drying, obtain the 9.74g copolymer.Embodiment 25. poly-(2-(trimethyl ammonium chloride) ethyl acrylate), copolymerization-(2-(trimethyl ammonium chloride) first
The base ethyl acrylate), copolymerization-styrene (TMAEAC copolymerization-TMAEMC copolymerization
-Sty) preparation
In flask at the bottom of the 1000mL three neck gardens, add following material: 2-(trimethyl ammonium chloride) ethyl acrylate (TMAEAC) (50% aqueous solution of 6.00g, 3.00g), 2-(trimethyl ammonium chloride) ethyl methacrylate (TMAEMC) (70% aqueous solution of 4.29g, 3.00g), divinyl benzene crosslinked comonomer (1.00g), styrene (13.00g), 2-propanol (150mL) and AIBN (0.50g).Gained solution is clarifying.Then, reactant mixture is heated to 70 ℃, outgases with nitrogen simultaneously.Solution begins muddiness after short time, shows that polyreaction carries out.To be reflected at 70 ℃ and keep 24 hours, be cooled to room temperature then.
Decantation resulting polymers, pulp in 500mL methanol immediately then.Mixture was stirred 0.5 hour.Filter polymer paste and add the 500mL distilled water.Mixture was stirred 0.5 hour and mixed 10 minutes.With mixture sedimentation and decantation water.Repeat water slurryization twice, use 400mL methanol pulp decantation residue at every turn, and each sedimentation and decantation.Vacuum drying obtains 8.03g title copolymer.Embodiment 26. poly-(methacrylamido propyl group-3-(trimethyl ammonium chloride)), copolymerization-(2-(trimethyl
Ammonium chloride) copolymerization ethyl acrylate) ,-(2,3,4,5,6-phenyl-pentafluoride ethylene) (MAPTAC
Copolymerization-TMAEAC copolymerization-StyF 5) preparation
In flask at the bottom of the 1000mL three neck gardens, add (MAPTA) (8.00g of following material: ethyl methacrylate-3-(trimethyl ammonium chloride), 50% aqueous solution, 4.00g), 2-(trimethyl ammonium chloride) ethyl acrylate (TMAEMA) (50% aqueous solution of 6.00g, 3.00g), divinyl benzene crosslinked comonomer (1.00g), phenyl-pentafluoride ethylene (12.00g), 2-propanol (150mL) and AIBN (0.50g).Gained solution is clarifying.Then, reactant mixture is heated to 70 ℃, outgases with nitrogen simultaneously.Solution begins muddiness after short time, shows that polyreaction carries out.To be reflected at 70 ℃ and keep 24 hours, be cooled to room temperature then.
Filter resulting polymers, and on funnel, use washed with isopropyl alcohol, pulp in 400mL methanol immediately then.Mixture is stirred 0.5.250mL water slurryization, twice are totally used in the polymer paste filtration then at every turn.Last polymer paste was mixed 5 minutes.Filtering mixt is used the pulp of 250mL methanol, twice totally then at every turn.Vacuum drying filtrate obtains the 7.80g copolymer.Embodiment 27. poly-(2-(trimethyl ammonium chloride) ethyl acrylate), copolymerization-(2-(trimethyl ammonium chloride) first
The base ethyl acrylate), copolymerization-(2,3,4,5,6-phenyl-pentafluoride ethylene) (TMAEAC copolymerization
-TMAEMC copolymerization-Sty F 5) preparation
In flask at the bottom of the 1000mL three neck gardens, add following material: 2-(trimethyl ammonium chloride) ethyl acrylate (TMAEAC) (50% aqueous solution of 6.00g, 3.00g), 2-(trimethyl ammonium chloride) ethyl methacrylate (TMAEMC) be (4.29g's, 70% aqueous solution, 3.00g), divinyl benzene crosslinked comonomer (1.00g), phenyl-pentafluoride ethylene (13.00g), 2-propanol (150mL) and AIBN (0.50g).Gained solution is clarifying.Then, reactant mixture is heated to 70 ℃, outgases with nitrogen simultaneously.Solution begins muddiness after short time, shows that polyreaction carries out.To be reflected at 70 ℃ and keep 24 hours, be cooled to room temperature then.
Decantation resulting polymers, pulp in 400mL methanol immediately then.Mixture was stirred 0.5 hour.Filter polymer paste, use the 200mL water slurryization then, twice totally at every turn.Polymer paste mixed 5 minutes for the second time.Filtering mixt is also each with the pulp of 200mL methanol, twice totally.Vacuum drying obtains 6.87g title copolymer.Embodiment 28. poly-(methacrylamidopropyltrimethyl trimethyl ammonium chloride) copolymerization (4-vinyl biphenyl)
(the preparation of MAPTAC copolymerization-VBPh)
In flask at the bottom of the 1000mL three neck gardens, add following material: methacrylamidopropyltrimethyl trimethyl ammonium chloride (MAPTAC) (50% aqueous solution of 10.49g, 0.0475mol), 4-vinyl biphenyl (VBPh) (9.01g, 0.050mol), divinyl benzene crosslinked comonomer (1.47g), 2-propanol (150mL), polymerization initiator AIBN (0.25g).The gained mixture contains insoluble VBPh (dissolving of heating back).Then, reactant mixture is heated to 70 ℃, outgases with nitrogen simultaneously.Solution begins muddiness after short time, shows that polyreaction carries out.To be reflected at 70 ℃ and keep 24 hours hours, be cooled to room temperature then.
Filter resulting polymers, and use washed with isopropyl alcohol on funnel, pulp in 200mL methanol immediately then then stirred 1 hour.Filter polymer paste, repeat methanol pulp step then.Then each with 200mL water slurry fluidized polymer, twice totally.Filter the gained mixture and then filter cake is used the pulp of 200mL methanol, twice totally then at every turn.Filter gained mixture and vacuum drying and obtain the 9.59g copolymer.Embodiment 29. poly-(methacrylamidopropyltrimethyl trimethyl ammonium chloride) copolymerization (4-vinyl biphenyl)
(the preparation of MAPTAC copolymerization-VA)
In flask at the bottom of the 1000mL three neck gardens, add following material: methacrylamidopropyltrimethyl trimethyl ammonium chloride (MAPTAC) (50% aqueous solution of 10.49g, 0.0475mol), 4-vinyl methoxybenzene (VA) (6.71g, 0.050mol), divinyl benzene crosslinked comonomer (1.30g), 2-propanol (200mL), polymerization initiator AIBN (0.40g).Then, the gained settled solution is heated to 70 ℃, outgases with nitrogen simultaneously.Solution begins muddiness after several hours, shows that polyreaction carries out.To be reflected at 70 ℃ and keep 36 hours, be cooled to room temperature then.
Filter resulting polymers, and use washed with isopropyl alcohol on funnel, pulp in 200mL methanol immediately then then stirred 1 hour.Filter polymer paste.Then each twice of 200mL water slurry fluidized polymer of using.Filter the gained mixture, filter cake with the pulp of 200mL methanol, is used 200 isopropyl alcohol pulps then.Filter gained mixture and vacuum drying and obtain the 5.19g copolymer.Embodiment 30. poly-[(N-(4-methyl styrene)-N '-(3-trimethyl ammonium chloride-2-hydroxypropyl) piperazine]
Preparation
The first step is the cinnamic reaction of preparation 4-(piperazinyl methyl).
In the 500mL flask, add vinyl chloride (7.63g, 0.050mol), piperazine (8.61g, 0.100mol) and isopropyl alcohol (50mL).The gained mixture 70 ℃ of heating 45 minutes, slowly is cooled to room temperature then so that form the slurry of crystalline material.This slurry is placed in the refrigerator about 3 hours, filters then.With solid piperazine hydrochloride vacuum drying, weigh then (5.55g) and discard.On rotary evaporator, mother solution is concentrated into about 25mL and adds ethyl acetate (50mL).The gained mixture is placed in the refrigerator about 10 minutes, the piperazine hydrochloride that obtains is for the second time filtered also discard then.Mother liquid evaporation is used it for preparation following N-(4-methyl styrene)-N '-(3-trimethyl ammonium chloride-2-hydroxypropyl) piperazine, and be need not to be further purified to the dried thick 4-of 10.35g (piperazine methyl) styrene that obtains on rotary evaporator.In the 500mL flask, add 4-(piperazine methyl) styrene (10.35g, about 0.45mol), and the glycidyl trimethyl ammonium chloride (7.58g, 0.045mol) and isopropyl alcohol (50mL).With gained mixture heated to 60 ℃ and stirred 20 hours, be cooled to room temperature then, and be used for following polyreaction and need not to be further purified.
Divinyl benzene crosslinked comonomer (0.93g) is added in 0.40mol N-(4-methyl styrene)-N '-(3-trimethyl ammonium chloride-2-hydroxypropyl) piperazine.With the degassing of gained solution, add polymerization initiator AIBN (0.20g) with nitrogen then.Temperature is risen to 70 ℃ of continuation with the nitrogen degassing and placed at this moment a large amount of cross linked polymer precipitations 3 hours.Then mixture is cooled to 40 ℃ and filtration.
Filter resulting polymers, and use washed with isopropyl alcohol on funnel, pulp in 200mL methanol immediately then then stirred 1 hour.Filter polymer paste, repeat methanol pulp step then.Each with 200mL water slurry fluidized polymer, twice totally.Then filter, filter cake is used the pulp of 200mL methanol at every turn, totally twice, vacuum drying obtains the 7.90g copolymer.Embodiment 31. poly-(N-(4-methyl styrene)-N '-(3-trimethyl ammonium chloride-2-hydroxypropyl) piperazine,
The preparation of co polystyrene
In 0.022mol N-(4-methyl styrene)-N '-(3-trimethyl ammonium chloride-2-hydroxypropyl) piperazine (pressing embodiment 30 described preparations), add styrene copolymerized monomer (2.29g, 0.022mol) and the divinyl benzene crosslinked comonomer (0.50g, 0.004mol).With the degassing of gained solution, add polymerization initiator AIBN (0.3g) with nitrogen then.Temperature is risen to 70 ℃, and continuation is with the nitrogen degassing and placed at this moment a large amount of cross linked polymer precipitations 4 hours.Add the 25mL isopropyl alcohol then and continue heating 19 hours.Afterwards, mixture is cooled to room temperature and filtration, obtains solid polymer.
Filter resulting polymers, and on funnel, use washed with isopropyl alcohol, pulp in 200mL methanol immediately then.Then, mixture was stirred 0.5 hour.Filter polymer paste, use 250mL water slurry fluidized polymer, twice totally at every turn.Filtering mixt, pulp in the 200mL isopropyl alcohol is then filtered in filter cake pulp in 200mL methanol.Filter and vacuum drying, obtain the 4.98g copolymer.
The styrene that contains 2: 1 mol ratios: quaternary ammonium monomer is also prepared with similar approach.Embodiment 32. poly-(the amino cinnamic preparations of N-(3-trimethyl ammonium chloride-2-hydroxypropyl)-4-
The first step is by following described preparation 4-amino methyl styrene.
In the 250mL flask, add vinyl chloride (7.63g, 0.050mol), strong aqua ammonia (9.8mL) and isopropyl alcohol (40mL).Mixture was stirred for 1 week, and at this moment mass crystallization material (ammonium chloride) precipitates.Leach solid and use washed with isopropyl alcohol.Mother solution evaporates on rotary evaporator up to can't smell the ammonia flavor.Add isopropyl alcohol (50mL), then with freezing several hours of mixture.After freezing, sedimentary 4-amino methyl styrene ammonium chloride is filtered off, and obtains 4-amino methyl styrene, need not to be further purified and can use.
In the 500mL flask, add 4-amino methyl styrene (0.050mol), the glycidyl trimethyl ammonium chloride (7.62g, 0.050mol) and water (about 2mL) formation solution, and adding divinyl cross-linking comonomer (0.98g).Gained solution 70 ℃ of heating 5 hours, afterwards, is added low amounts of water (about 5-10mL) to dissolve some sedimentary salt.Add polymerization initiator AIBN (0.20g), outgas to solution with nitrogen simultaneously.It is very thick that at this moment reactant mixture has become, needs to add isopropyl alcohol polymer can be stirred.
After 16 hours, mixture is cooled to room temperature and filtration at 70 ℃ of stir abouts.Resulting polymers is used methanol wash on funnel, then pulp in 200mL methanol immediately.Then, the gained mixture was stirred 1 hour.Filter polymer paste, repeat the pulp process again one time with methanol.Then, polymer is with the pulp of each 200mL methanol, twice totally.Filtering mixt, filter cake pulp in 200mL methanol.Filter and vacuum drying, obtain the 8.68g polymer.Embodiment 33. usefulness 1-iodo-octane alkylating agents will with the di-2-ethylhexylphosphine oxide Methacrylamide crosslinked poly-(two
Methylamino propyl methyl amide) alkylation
With (1.0g) being suspended in the methanol (100mL) of the described methods preparation of embodiment 5, and add sodium hydroxide (0.2g) with crosslinked poly-(the dimethylamino-propyl Methacrylamide) of di-2-ethylhexylphosphine oxide Methacrylamide.Stir after 15 minutes, add 1-iodo-octane (1.92mL), and mixture was stirred 20 hours at 60 ℃.Then, cooling mixture leaches solid.By solid suspension is washed it in isopropyl alcohol (500mL).Afterwards, stirred 1 hour and collect by filtering.With sodium-chloride water solution (the 1M solution of 500mL) repeated washing process twice, water (500mL) washing, totally twice, with isopropyl alcohol (500mL) washing once.Drying is 24 hours in 50 ℃ of vacuum drying ovens, obtains the 0.1g alkylation products.Embodiment 34. usefulness 1-iodo-octane alkylating agents will with the di-2-ethylhexylphosphine oxide Methacrylamide crosslinked poly-(two
Methylamino propyl group acrylamide) alkylation
According to embodiment 33 described methods will with the described methods preparation of embodiment 4 with crosslinked poly-(dimethylamino propyl acrylamide) (10g) alkylation of di-2-ethylhexylphosphine oxide Methacrylamide, obtain the 2.95g alkylation products.Embodiment 35. poly-(2-(methacrylamido) ethyl-trimethyl ammonium iodide) copolymerization-cinnamic system
Be equipped with
The first step is by following described preparation 2-(N ', N '-dimethylamino)-N-ethyl-methyl acrylamide hydrochlorate.
In the 1000mL flask, add methacrylic chloride (52.3g, 0.5mol) and oxolane (300mL).Solution is cooled to below 10 ℃, drips N then, (30.5g, oxolane 0.35mol) (100mL) maintain the temperature at 8-10 ℃ to N-dimethylamino ethamine simultaneously.Add and to finish the after-filtration mixture, wash with cold oxolane, vacuum drying obtains 65.69g 2-(N ', N '-dimethylamino)-N-ethyl-methyl acrylamide hydrochlorate.
Next step is preparation 2-as described below (methacrylamido) ethyl-trimethyl ammonium iodide.
With potassium hydroxide (15.4g, 0.24mol) and methanol (240mL) put into the 500mL flask, then mixture is fully stirred potassium hydroxide is dissolved fully.(46.35g 0.24mol), and stirs the gained mixture 0.5 hour to add 2-(N ', N '-dimethylamino)-N-ethyl-methyl acrylamide hydrochlorate in solution.Filtering mixt is to remove potassium chloride.Filtrate concentrates in rotary evaporator.With isopropyl alcohol (400mL) and methyl iodide (18.7mL, 42.6g 0.30mol) are added in the spissated filtrate, then with mixture in stirred overnight at room temperature.In second day morning, the solid product that leaches is used washed with isopropyl alcohol, and vacuum drying obtains 61.08g 2-(methacrylamido) ethyl-trimethyl ammonium iodide, is white crystalline solid.
Then, with 2-(methacrylamido) ethyl-trimethyl ammonium iodide (12.24g, 0.050mol), styrene (5.2g, 0.050mol), divinyl benzene crosslinked comonomer (0.65g, 0.005mol), isopropyl alcohol (150mL), water (20mL) and polymerization initiator AIBN (0.4g) are added in the 1000mL flask.Give the degassing of gained solution with nitrogen, be heated to 70 ℃ simultaneously.Then, solution was stirred 24 hours under 70 ℃ and nitrogen, afterwards, it is cooled to room temperature.At this moment, the decantation solvent is added to 200mL methanol then and forms serosity in the flask, and stirs and spend the night.Filtration product is added to then in the agitator and mixes with 500mL water.Stir and closed the gained mixture 15 minutes, filter then.Water (200mL) and methanol (200mL) wash the solid matter that stays successively.Filter and vacuum drying, obtain the 3.22g title polymer. The polymer testA. artificial intestinal juice's preparation test method 1
Sodium carbonate (1.27g) and sodium chloride (1.87g) are dissolved in the 400mL distilled water.Add pure bile acid mixture to this solution; this mixture is by taurocholic acid (0.138g; 0.24mmol); glycocholic acid (0.292g; 0.60mmol); glycodesoxycholic acid (0.085g, 0.18mmol) and glycochenodeoxycholate (glycochenodeoxycholic) (0.085g 0.18mmol) forms.With acetic acid the pH of solution is transferred to 7.20.This solution is used to the test of multiple polymers.The concentration of whole bile saltss is 3 mMs in this solution, and this concentration is approximately equal to the concentration of normal body fluid in the duodenum.
The polymer test is as follows.
The artificial intestinal fluid of 20mL that in the 40mL centrifuge tube, adds the 0.25g polymer and above prepare.With mixture in the stirred in water bath 3 hours that remains in 37 ℃.Mixture is centrifugal, and filter a bit muddy supernatant.By carrying out total 3-hydroxy steroids content (as described below) that enzymatic determination is analyzed filtrate with 3a-hydroxyl steroid dehydrogenase.Test method 2
Sodium carbonate (1.27g) and sodium chloride (1.87g) are dissolved in the 400mL distilled water.In this solution, add glycocholic acid (1.95g, 4.0mmol) or glycochenodeoxycholate (1.89g 4.0mmol), makes 10mM solution.With acetic acid the pH of solution is transferred to 6.8.These stock solutions are used to the test of multiple polymers.
The polymer test is as follows.
In the 14mL centrifuge tube, add the 10mg polymer and from 10mM liquid storage (preparation as above) preparation, concentration is the 10mL bile salts solution of 0.1-10mM, and an amount of anacholia salt buffer.With mixture in the stirred in water bath 3 hours that remains in 37 ℃.Filtering mixt.By carrying out total 3-hydroxy steroids content (as described below) that enzymatic determination is analyzed filtrate with 3 Alpha-hydroxy steroid dehydrogenases.
The enzymatic determination of total bile salt levels
Prepare four kinds of liquid storages.
Solution 1:Tris-HCl buffer contains 0.133M Tris, 0.666mM EDTA,
pH9.5。
Solution 2: hydrazine hydrate solution contains 1M pH and is 9.5 hydrazine hydrate.
Solution 3:NAD+ solution contains 7mM NAD+, pH7.0.
Solution 4:HSD solution, contain 2 units/mL the Tris-HCl buffer (0.03M Tris,
1mM?EDTA)，pH7.2。
In the 3mL cuvette, add 1.5mL solution 1,1.0mL solution 2,0.3mL solution 3, supernatant/filtrate that the above-mentioned polymer test of 0.1mL solution 4 and 0.1mL obtains.This solution is placed the UV-VIS spectrophotometer and measure its NADH absorption (O.D.) at the 340nm place.Bile salt concentration is measured by the artificial intestinal juice's dilution factor calibration curve for preparing above.
Foregoing whole polymer has all been participated in above-mentioned one or two test, and all effective to remove bile salts from the artificial intestinal juice. Use
Polymer of the present invention can about 1mg/kg/ days to about 10g/kg/ days dosage to patient's oral administration.Concrete dosage depends on each patient's situation, as patient's the weight and the scope of the bile salts that will remove.Polymer can hydrate or non-hydrate form administration, if desired, can also add flavoring agent to increase patient's ability to accept.The composition that can add is also just like the artificial coloring in addition.
The example that is suitable for administration comprises pill, tablet, wafer and powder (as being sprayed on the food).These pills, tablet, wafer, or powder can be with the material coating that protective capability is arranged, and this substance protection compositions is not influenced by the gastric acid in patient's stomach, does not arrive at patient's small intestinal to obtain the long enough time with not being decomposed.This polymer can be alone or with pharmaceutically acceptable carrier mass such as magnesium carbonate or lactose administration, or polymer and phospholipid form micella.
Other specifies and is included in the claim of the present invention.

Claims (29)

1. one kind is used to make the polymer composition of removing the medicine of bile salts by ion exchange in patient's body, comprises the product of the following substances for the treatment of effective dose:
(a) one or more have the cross linked polymer of following formula repetitive:
Figure C9519352200021
Or its salt and its co-polymer, wherein n is an integer; R 1Be H or C 1-C 8Alkyl; M is Or-Z-R 2Z is O, NR 3, S, or (CH 2) mM=0-10; R 3Be H or C 1-C 8Alkyl; And R 2Be Or
Figure C9519352200024
Wherein P=0-10, and R 4And R 5, be H; R 6Be H, C 1-C 8Alkyl, or aryl; With
(b) at least a alkylating reagent, wherein said polymer is crosslinked by multifunctional cross-linking reagent, and the amount of described reagent accounts for the 1-25% weight ratio of total monomer weight; Described alkylating reagent has formula RX, and wherein R comprises C 1-C 20Alkyl, C 1-C 20Hydroxy alkyl, C 1-C 20Aralkyl, C 1-C 20Alkylammonium, or C 1-C 20Alkyl amido, and X comprises one or more electrophilic leaving groups.
2. polymer composition according to claim 1, wherein said polymer is crosslinked by multi-functional cross-linking comonomer.
3. polymer composition according to claim 2, wherein said cross-linking comonomer are the 2.5-20% of total monomer weight.
4. one kind is used to make the polymer composition of removing the medicine of bile salts by ion exchange in patient's body, comprises the product of the following substances for the treatment of effective dose, and (a) one or more cross linked polymers comprise repeating unit represented:
Figure C9519352200031
Or its salt and its copolymer, wherein n is an integer, p=0-10, R 1Be that H or C1 are to C8 alkyl group, R 4And R 5Each is H, and C1 is to the C8 alkyl or aryl; (b) at least two kinds of alkylating reagents, wherein (i) a kind of described alkylating reagent has chemical formula RX, wherein R is that C1 is to the C20 alkyl, X is one or more electrophilicity leaving groups, another kind of described alkylating reagent has chemical formula R ' X, wherein R ' be C1 to the C20 alkyl ammonium group, X is one or more electrophilic leaving groups; Or (ii) a kind of described alkylating reagent has chemical formula RX, wherein R be C1 to the C20 alkyl, X is one or more electrophilicity leaving groups, another kind of described alkylating reagent has chemical formula R ' X, wherein R ' be C1 to the C20 hydroxyalkyl, X is one or more electrophilic leaving groups; (iii) a kind of described alkylating reagent be C1 to the C20 alkylene dihalide, another kind of described alkylating reagent is that C1 is to the C20 alkylammonium salt.
5. polymer composition according to claim 4, wherein said repetitive (a) has following formula Or its salt or its copolymer.
6. polymer composition according to claim 4, wherein said repetitive (a) has following formula Or its salt or its copolymer.
7. one kind is used to make the polymer composition of removing the medicine of bile salts by ion exchange in patient's body, comprises the product of the following substances for the treatment of effective dose, and (a) one or more cross linked polymers comprise repeating unit represented:
Figure C9519352200042
Or its salt or its copolymer, wherein R 1Be H or C1 to the C8 alkyl, n is an integer, and p=0-10; And (b) at least two kinds of alkylating reagents, wherein (i) a kind of described alkylating reagent has chemical formula RX, wherein R is that C1 is to the C20 alkyl, X is one or more electrophilicity leaving groups, another kind of described alkylating reagent has chemical formula R ' X, wherein R ' be C1 to the C20 alkyl ammonium group, X is one or more electrophilic leaving groups; Or (ii) a kind of described alkylating reagent has chemical formula RX, wherein R be C1 to the C20 alkyl, X is one or more electrophilicity leaving groups, another kind of described alkylating reagent has chemical formula R ' X, wherein R ' be C1 to the C20 hydroxyalkyl, X is one or more electrophilic leaving groups; (iii) a kind of described alkylating reagent be C1 to the C20 alkylene dihalide, another kind of described alkylating reagent is that C1 is to the C20 alkylammonium salt.
8. one kind is used to make the polymer composition of removing the medicine of bile salts by ion exchange in patient's body, comprises the product of the following substances for the treatment of effective dose, and (a) one or more cross linked polymers comprise repeating unit represented:
Figure C9519352200051
Or its salt or its copolymer, wherein R 1Be H or C1 to the C8 alkyl, n is an integer, p=1-10; (b) at least a alkylating reagent, described alkylating reagent has formula RX, and wherein R comprises C 1-C 20Alkyl, C 1-C 20Hydroxy alkyl, C 1-C 20Aralkyl, C 1-C 20Alkylammonium, or C 1-C 20Alkyl amido, and X comprises one or more electrophilic leaving groups.
9. polymer composition according to claim 1, wherein said repetitive (a) has following formula
Figure C9519352200052
Or its salt and its co-polymer, wherein Z is NR 3Or (CH 2) m, R 2Be Or And R 1, R 3, R 4, R 5, R 6, n, m and p such as claim 1 definition.
10. according to the described polymer composition of claim 1,7 or 8, wherein said polymer also contains one or more tradable counterbalances.
11. polymer composition according to claim 10, wherein one of described at least counterbalance comprises Cl -, Br -, CH 3OSO 3 -, HSO 4 -, SO 4 2-, HCO 3 -, CO 3 2-, acetate, lactate, succinate, propionate, butyrate, Ascorbate, citrate, maleate, folate, amino acid derivativges, nucleotide, lipoid, phospholipid.
12. polymer composition according to claim 11, wherein said X comprises halogenide, epoxide, benzene methanesulfonic acid salt, or mesylate group.
13. polymer composition according to claim 12, wherein said alkylating reagent comprises C 4-C 20Alkyl halide.
14. polymer composition according to claim 12, wherein said alkylating reagent comprises C 1-C 20The alkyl halide ammonium salt.
15. polymer composition according to claim 12, wherein said alkylating reagent is C 1-C 20The dihalo alkyl, C 1-C 20Hydroxy alkyl halogen, C 1-C 20Aralkyl halogen, C 1-C 20Alkyl epoxy base ammonium salt, or C 1-C 20The epoxy radicals alkylamide.
16. one kind is used to make the polymer composition of removing the medicine of bile salts by ion exchange in patient's body, comprises the product of the following substances for the treatment of effective dose:
(a) one or more have the cross linked polymer of following formula repetitive:
Figure C9519352200071
Or its salt and its co-polymer, wherein n is an integer; R 1Be H or C 1-C 8Alkyl; M is
Figure C9519352200072
Or-Z-R 2Z is O, NR 3, S, or (CH 2) mM=0-10; R 3Be H or C 1-C 8Alkyl; And R 2Be
Figure C9519352200073
Or
Figure C9519352200074
Wherein P=0-10, and R 4, R 5Or R 6Each is H, C 1-C 8Alkyl, or aryl; With
(b) at least two kinds of alkylating reagents, one of described alkylating reagent has formula RX, and wherein R is C 1-C 20Alkyl, X comprise one or more electrophilic leaving groups, reach another alkylating reagent and have formula R ' X, and wherein R ' is C 1-C 20Alkylammonium, X comprise one or more electrophilic electronics leaving groups, and condition is R 2Comprise R 4, R 5And R 3, R 4, R 5And R 3In at least one is H.
17. one kind is used to make the polymer composition of removing the medicine of bile salts by ion exchange in patient's body, comprises the product of the following substances for the treatment of effective dose:
(a) one or more have the cross linked polymer of following formula repetitive:
Figure C9519352200081
Or its salt and its co-polymer, wherein n is an integer; R 1Be H or C 1-C 8Alkyl; M is Or-Z-R 2Z is O, NR 3, S, or (CH 2) mM=0-10; R 3Be H or C 1-C 8Alkyl; And R 2Be Or Wherein P=0-10, and R 4, R 5Or R 6Each is H, C 1-C 8Alkyl, or aryl; With
(b) at least two kinds of alkylating reagents, one of described alkylating reagent has formula RX, and wherein R is C 1-C 20Alkyl, X comprise one or more electrophilic leaving groups, reach another alkylating reagent and have formula R ' X, and wherein R ' is C 1-C 20Hydroxy alkyl, X comprise one or more electrophilic leaving groups, and condition is R 2Comprise R 4, R 5And R 3, R 4, R 5And R 3In at least one is H.
18. one kind is used to make the polymer composition of removing the medicine of bile salts by ion exchange in patient's body, comprises the product of the following substances for the treatment of effective dose:
(a) one or more have the cross linked polymer of following formula repetitive: Or its salt and its co-polymer, wherein n is an integer; R 1Be H or C 1-C 8Alkyl; M is
Figure C9519352200092
Or-Z-R 2Z is O, NR 3, S, or (CH 2) mM=0-10; R 3Be H or C 1-C 8Alkyl; And R 2Be
Figure C9519352200093
Or
Figure C9519352200094
Wherein P=0-10, and R 4, R 5Or R 6Each is H, C 1-C 8Alkyl, or aryl; With
(b) at least two kinds of alkylating reagents, one of described alkylating reagent is C 1-C 20Saturated dihalide, and another alkylating reagent is C 1-C 20Alkylammonium salt, condition are R 2Comprise R 4, R 5And R 3, R 4, R 5And R 3In at least one is H.
19. one kind is used to make the polymer composition of removing the medicine of bile salts by ion exchange in patient's body, comprises the cross linked polymer with following formula repetitive of taking one or more treatment effective doses to the patient
Figure C9519352200101
Or its copolymer, wherein n is an integer, R 1Be H or C 1-C 8Alkyl; L is
-NH-or
G is Or
And each R 2, R 3And R 4Each is H naturally, C 1-C 8Alkyl, or aryl.
20. polymer composition according to claim 19, wherein said polymer is crosslinked by multi-functional cross-linking comonomer, and described comonomer is about the 1-25% of total monomer weight.
21. polymer composition according to claim 20, wherein said cross-linking comonomer are the 2.5-20% of total monomer weight.
22. polymer composition according to claim 19, wherein said polymer also comprises one or more hydrophobic comonomers.
23. polymer composition according to claim 22, wherein said hydrophobic comonomer comprises styrene and fluorinated derivatives thereof; Vinyl xylene, ethyl vinyl benzene and fluorinated derivatives thereof; The N-alkyl of acrylamide and Methacrylamide and N-aryl derivatives and fluorinated derivatives thereof; Acrylic acid alkyl and aryl ester and fluorinated derivatives thereof; The alkyl of methacrylic acid and aryl ester and fluorinated derivatives thereof; 4-vinyl biphenyl and fluorinated derivatives thereof; 4-vinyl methoxybenzene and fluorinated derivatives thereof; With 4-aminobenzene ethylene and fluorinated derivatives thereof.
24. being characterised in that, polymer composition according to claim 19, wherein said polymer have the following formula repetitive
Figure C9519352200111
Or its copolymer, wherein n and G such as claim 19 definition.
25. being characterised in that, polymer composition according to claim 19, wherein said polymer have the following formula repetitive
Figure C9519352200112
Or its copolymer, wherein n and G such as claim 19 definition.
26. polymer composition according to claim 19, wherein said polymer comprises the repetitive with following formula
Figure C9519352200113
Or its copolymer, wherein said n such as claim 19 definition.
27. polymer composition according to claim 19 also comprises styrene or its fluorinated derivatives as comonomer.
28. polymer composition according to claim 19, wherein said polymer comprises the repetitive with following formula
Figure C9519352200121
Or its copolymer, wherein said n such as claim 19 definition.
29. one kind is used to make the polymer composition of removing the medicine of bile salts by ion exchange in patient's body, comprises the product of the following substances for the treatment of effective dose:
(a) one or more have the cross linked polymer of following formula repetitive: Or its salt and its co-polymer, wherein n is for whole; R 1Be H or C 1-C 8Alkyl; M is Or-Z-R 2Z is O, NR 3, S, or (CH 2) mM=0-10; R 3Be H or C 1-C 8Alkyl; And R 2Be
Figure C9519352200124
Or
Figure C9519352200125
Wherein P=0-10, and R 4, R 5Or R 6Each is H, C 1-C 8Alkyl, or aryl; With
(b) at least a alkylating reagent, one of described alkylating reagent has formula RX, and wherein R comprises C 4-C 20Alkylammonium, X comprise one or more electrophilic leaving groups, and condition is R 2Comprise R 4, R 5And R 3, R 4, R 5And R 3In at least one is H.The application of polymer composition during preparing the medicine of in patient's body, removing bile salts as one of claim 1-29.
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